DOI 10.1007/s12247-008-9032-4
Introduction
The International Society for Pharmaceutical Engineering
(ISPE) launched the Product Quality Lifecycle Implementation (PQLI) initiative in June 2007 in US [1] and a
follow-up workshop was held in Europe in September [2].
The intention of PQLI is to work with industry and
regulatory agencies worldwide to facilitate a common
understanding of Quality-by-Design (QbD), and introduce
pragmatic and practical means for the implementation of
ICH guidances, based on sound scientific, engineering and
business principles. The emphasis will initially be on
providing how to implementation guidance on ICH Q8,
Q8 (R), Q9 and Q10 [36]. It will embrace science and
engineering, cover small and large molecules, and address
both drug substance and drug product.
PQLI outputs are not regulatory documents. They try to
capture best practice and draw their sources from open
intra-industry and regulatory discussions aimed at practical
solutions to ensure product quality, and as such this paper
represents a work-in-progress. It is important to note that
PQLI is not in place of or in competition with the ICH
process and its goals. Rather, it is a process committed to
helping out with the implementation of ICH guidance.
PQLI issued a summary update report September 14,
2007 [7], which coincided with the European ISPE PQLI
Conference in Berlin, Germany. Additional discussions on
the task teams progress with regulators from the US,
Europe and Japan occurred at the 2007 ISPE Annual
Meeting [8, 9]. During this conference, opportunities to
broaden the program to biotechnology products were also
explored. A further major workshop was held during the
ISPE Congress in Copenhagen [16].
This document provides an overview of the progress
thus far for the Criticality, Design Space, and Control
Strategy task teams. It is part of a suite of documents to be
produced by ISPE.
Background
In discussing the Desired State1 Janet Woodcock [10, 17]
described Quality by Design (QbD) as encompassing the
development of scientific understanding of critical process
and product attributes, designing controls and testing based
on the limits of scientific understanding at development
stage, and utilizing the knowledge gained over the
products lifecycle to operate in an environment of
continuous improvement. Recently, the International Conference on Harmonization (ICH) has defined QbD in ICH
Q8R as a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding based on sound
science and quality risk management.
Some elements of QbD have been used for many years.
For example, the use of statistically designed experiments
(DOE) dates back to the 1920s as factorial designs were
applied in agricultural science, and the 1950s when they
were more widely used for industrial applications. FMEA, a
commonly used risk assessment tool, was developed by the
United States Military to assess equipment and system
failures [11]. In the 1990s, software was developed that
combined risk assessment and DOE techniques. The
spotlight on these techniques has intensified in the
pharmaceutical industry, in particular with the United States
Food and Drug Administrations (FDA) issuance of their
report Pharmaceutical CGMPs for the 21st Century: A
Risk-Based Approach; A Science and Risk-Based Approach to Product Quality Regulation Incorporating an
Integrated Quality Systems Approach [12]. This report
launched a strategic change towards the presentation of
more scientific knowledge in submissions, thereby laying
the groundwork for QbD. Shortly afterwards, FDA issued
the guidance document, PAT A Framework for
Innovative Pharmaceutical Development, Manufacturing,
and Quality Assurance [13]. Although the focus was more
geared towards process analytical technology (PAT), this
guidance document discussed many principles of QbD.
Subsequent papers followed, such as the EMEA PAT
1
61
3
ICH Q10 defines a Pharmaceutical Quality System as a management system to direct and control a pharmaceutical company with
regard to quality.
62
63
Control Strategy
based on
Criticality
Assessment of
Variables
YES
Knowledge
Space & Quality
Systems Support RiskBased Control
Strategy?
NO
Control Strategy
Based on
Traditional
Specification
Setting
Foundational
Developmental
Potential
For Variables
To Impact
Quality?
NO
Non-Critical
LOW RISK
YES
HIGH RISK
Critical
Legend
Foundational Classification Business decision
Business Decision determines QbD vs. traditional
approach
Developmental Classification Quality decision
Risk Assessment Decision categorizes initial designation
to distinguish non-critical from potentially critical based on
functional relationships to Critical Quality Attributes
Non-Critical
Critical
5
Univariate analysis is an approach that may contribute to the creation
of a design space. However, its application in conjunction with
multivariate approaches may warrant additional studies to address
interactions.
64
Design Space
The development and refinement of the Design Space
begins at product conceptualization and continues to evolve
throughout the lifecycle of the product. At the time of filing
a submission, the Design Space can be considered to be a
snap-shot in time representative of the current process
knowledge. It continues to evolve as additional knowledge
and information is generated during the commercialization
of the product, which may lead to post-approval changes.
Movement out of the Design Space is considered to be a
change and would normally initiate a regulatory post
approval change process. As such, the Design Space will
require management under a companys Pharmaceutical
Quality System.
The creation of a Design Space begins with the
definition of the Pharmaceutical Target Product Profile
(PTPP)6, which identifies the desired performance characteristics of the product. Prior knowledge and a preliminary
risk assessment can be used to identify experiments to be
ICH Q8R defines a PTPP as being a prospective and dynamic
summary of the quality characteristics of a drug product that ideally
will be achieved to ensure that the desired quality, and hence the
safety and efficacy, of a drug product is realised.
65
Lubrication &
Compression
Parameters
Parameters
Parameters
Parameters
Preblend Time
Target: X min
Range: X-Y min
Lubricant Mixing
Time: X-Y min
Bin Loading
X-Y% Fill
Order of Addition
of API
Formulation &
Process Devel
Preblending
& Milling
Parameters
Prior Knowledge
Excipient Grade
Particle Size
Excipient Compatability Studies
API Particle Size
VMD < X m
Gap Width
X-Y mm (Gerteis)
Compression
Force: X-Y kN
Press Shut-Off:
nlt X kg Blend
Remaining
Gran. Speed:
X-Y rpm
Attributes
Blend Segregation
Sieve Cut Uniformity
PS of Granulation
Content
Uniformity
of Premix
Critical Process Parameter
Attributes
# Spray Guns
Attributes
Physical Properties
of Tablets
Twinning
Appearance
(Logo Erosion)
% By-Pass
Content Uniformity
of Final Blend
Jogging Cycle
X sec on / Y sec off
Attributes
Attributes
Film-Coating
Content Uniformity
Of Tablets
Stability
Control Strategy
ICH Q10 defines a control strategy as
a planned set of controls derived from current product
and process understanding that assures process performance and product quality. The controls can include
parameters and attributes related to drug substance and
drug product materials and components, facility and
equipment operating conditions, in process controls,
finished product specifications and the associated
methods and frequency of monitoring and control.
Control Strategy is not a new concept - products have
always had a more or less explicit control strategy - but in
ICH Q8(R) (Step 2) document a Minimal Approach to
Control Strategy is contrasted with the Enhanced, Quality
by Design Approach. In the latter, the control strategy is
closely linked to both criticality and the Design Space.
66
Fig. 5 Drug product design
space for an oral solid dosage
form
Formulation &
Process Devel
Preblending
& Milling
Lubrication &
Compression
Film-Coating
Parameters
Parameters
Parameters
Parameters
Parameters
Press Shut-Off:
nlt X kg Blend
Remaining
Attributes
Attributes
Attributes
Attributes
Attributes
Content Uniformity
Of Tablets
Content Uniformity
of Final Blend
Formulation &
Process Devel
Preblending
& Milling
Parameters
Parameters
1) API Specification
2) PAR for process
parameters that
impact particle size
PAR
PAR
PAR
Lubrication &
Compression
Film-Coating
Parameters
Parameters
Parameters
Sensor in hopper to
shut press off with X
kg remaining
Press Shut-Off:
nlt X kg Blend
Remaining
Attributes
PAR of process
parameters
impacting the QA
PAR of process
parameters
impacting the QA
Attributes
Attributes
Attributes
Attributes
Sieve Cut Uniformity
1) PAR, or
2) NIR Analysis
of Blending
Processes
PS of Granulation
PAR of process
parameters
impacting the QA
% By-Pass
Content Uniformity
of Final Blend
Content Uniformity
Of Tablets
1) Stratified Sampling
of Tablet Cores, or
2) Online NIR Analysis
&
&
&
&
67
References
1. Product quality lifecycle implementation: practical approach to
QbD, ISPE Washington Conference, Arlington, VA, 67 June,
2007.
2. Product Quality Lifecycle Implementation (PQLI): Practical
approach to quality by design, ISPE 2007 Berlin Conference,
Berlin, Germany, 19-September-2007.
3. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, ICH
Harmonised Tripartite Guideline, Pharmaceutical Development
Q8, Step 4, 10-November-2005.
4. International Conference on Harmonisation, ICH Draft: Step 1,
Q8 (R1) Pharmaceutical development revision 1, Step 3,
November 2007.
5. International Conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, ICH
harmonised tripartite guideline, quality risk management Q9, Step
4, 9-November-2005.
6. International Conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, ICH
harmonised tripartite guideline, pharmaceutical quality system
Q10, Step 2, 9-May-2007.
7. Draft PQLI summary update report, Version V04, product quality
lifecycle implementation (PQLI), ISPE, 14-September-2007,
http://www.ispe.org/cs/pqli_product_quality_lifeycle_implementation_/draft_pqli_summary_update_report.
8. E-RC3a - Product Quality Lifecycle Implementation (PQLI): a
practical approach to QbD, 2007 ISPE Annual Meeting, 5November-2007, Las Vegas, Nevada.
9. E-RC3b - PQLI design qualification and design review (Continued), 2007 ISPE Annual Meeting, 6-November-2007, Las Vegas,
Nevada.
68
10. Janet Woodcock, pharmaceutical quality in the 21st century - an
integrated systems approach, AAPS workshop: pharmaceutical
quality assessment - a science and risk-based CMC approach in
the 21st Century, North Bethesda, MD, 5-October-2005.
11. Procedures for performing a failure mode, effects and criticality
analysis, United States Military Procedure MIL-P-1629, 9-November-1949.
12. Pharmaceutical CGMPs for the 21st century: a risk-based
approach; a science and risk-based approach to product quality
regulation incorporating an integrated quality systems approach,
United States Department of Health and Human Services, U.S.
Food and Drug Administration, 21-August-2002 (http://www.fda.
gov/oc/guidance/gmp.html).
13. PAT - A framework for innovative pharmaceutical development,
manufacturing, and quality assurance, United States Department
of Health and Human Services, U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center
for Veterinary Medicine (CVM), Office of Regulatory Affairs
(ORA), Pharmaceutical CGMPs, September 2004.
14. EMEA PAT Team Position Paper, http://www.emea.europa.eu/
Inspections/docs/PATGuidance.pdf